Immune-suppressing drug reverses symptoms of delirium in mice

Investigators from the departments of Neurology, Neurosurgery, Psychiatry, Medicine, and Biomedical Sciences at Cedars-Sinai have shown that an immune-suppressing drug similar to one used to treat severe COVID-19 reversed symptoms of delirium in mice whose lungs were injured during mechanical breathing assistance. Their study, published in the peer-reviewed journal Critical Care, could pave the way for clinical testing of immune-inhibiting therapy for ventilation-induced delirium in patients.

Delirium, a serious condition resulting in confusion and reduced awareness of a person's environment, develops in more than 70% of patients placed on mechanical ventilation, said Shouri Lahiri, MD, director of the Neurosciences Critical Care Unit and Neurocritical Care Research at Cedars-Sinai and senior author of the study.

"Delirium is a significant clinical problem, but we have very limited tools for treating it," Lahiri said. "This work in mice gives us insight into the biology of the condition and, for the first time, gives us a pathway to directly test potential treatments."

Ventilator-induced delirium is common and can be unavoidable in patients with serious lung damage or disease-;including severe cases of COVID-19. That is because injury to the lung tissue causes inflammatory proteins to travel through the blood to the brain, resulting in confusion and disorientation.

"These inflammatory proteins help regulate the body's response to injury and infection, and here we show that by blocking these proteins in the blood, we interrupt their pathway to the brain and reverse the delirium so commonly experienced by patients," Lahiri said.

In the study, Lahiri and his team administered an IL-6 receptor function-blocking monoclonal antibody, which is similar to an immunosuppressive drug called tocilizumab that is given to patients with severe COVID-19, to mice with ventilator-induced lung injury. They observed changes in the brains of the mice, and also signs of delirium in their behavior in specially designed mazes.

"We showed that when we inhibited immune response in these mice, their delirium-associated brain changes and behavior improved," Lahiri said. "That's important because we tie changes in the brain to behavior."

In previous work, Lahiri and his team also established a connection in mice between immune response and delirium associated with urinary tract infection.

These collective findings shed light on changes in the brain that are associated with symptoms of delirium in critically ill patients. They also make clear the need to further investigate the important role of immunosuppressive therapy as a treatment for the debilitating delirium that so commonly follows ventilator use and common infections such as urinary tract infections."

Nancy L. Sicotte, MD, Chair of the Department of Neurology and the Women's Guild Distinguished Chair in Neurology

Lahiri said that future studies will investigate whether immune-suppressing therapy, in addition to reversing delirium in the short term, could have long-term benefits.

"It is well known that delirium could have long-term benefits associated with long-term cognitive impairment and accelerates long-term cognitive decline," Lahiri said. "And we know that by mitigating delirium, we will likely have an effect on long-term cognitive decline. The inflammatory response associated with COVID-19 also leaves a footprint that persists in the brain, so I think these immune-modulating therapies may also help ameliorate long COVID."